(171b) Local Delivery of rhBMP-2 from a Compression-Resistant Graft in a Canine Lateral Ridge Augmentation Model

Authors: 
Talley, A. D., Vanderbilt University
Kalpakci, K. N., Medtronic, Inc
Zienkiewicz, K., Vanderbilt University
Cochran, D. L., University of Texas Health Science Center San Antonio
Guelcher, S. A., Vanderbilt University

Statement of Purpose: Large mandibular defect reconstruction presents a continual challenge in oral and maxillofacial surgery. Growth factors such as recombinant human bone morphogenetic protein-2 (rhBMP-2) incorporated in scaffolds for tissue engineering promote cellular infiltration, induce osteoblast differentiation, and enhance new bone formation. RhBMP-2 is often delivered via an absorbable collagen sponge (ACS), but this may require a secondary space maintenance system, such as titanium mesh or polymer membrane1. Biodegradable polyurethane (PUR) biocomposites are reported to be effective carriers for rhBMP-2 and support new bone growth2. Mastergraft ceramic (CM) is an osteoconductive, biphasic ceramic with mineral content similar to bone. PUR/CM composites are osteoconductive and have sufficient stiffness to resist soft tissue prolapse. In the present study, we investigated space maintenance and new bone formation with an injectable PUR/CM composite with and without rhBMP-2 in a canine lateral ridge augmentation model.

Methods: The biodegradable PUR was synthesized from a lysine triisocyanate (LTI) and polyethylene glycol (PEG) prepolymer, a polyester triol (450 g/mol), and triethylene diamine catalyst. Treatment groups included the composite containing 45 wt% CM with no rhBMP-2, a low dose of 200 µg/mL rhBMP-2, or a high dose of 400 µg/mL rhBMP-2 (n=4/group). An ACS with a titanium mesh incorporating 400 µg/mL rhBMP-2 was used as a clinical control. For the PUR composites, lyophilized rhBMP-2 was hand-mixed with the PUR and injected into a lateral ridge defect (2/animal)  measuring approximately 13-14 mm mesiodistally, 8-9 mm apico-coronally, and 3-4 mm bucco-lingually. The volume of the injected graft allowed for the expansion to 45-55% porosity to fill the defect space, which occurred within a set time of 7-9 min. After this time, the soft tissue was closed over the defect. For the ACS samples, the rhBMP-2 was resuspended in sterile water and absorbed on the collagen sponge for 15 min prior to placement in the defect. A piece of titanium mesh was fastened over the sponge to prevent soft tissue prolapse. Animals were sacrificed at 16 weeks and new bone formation evaluated by radiographs, µCT, histology, and histomorphometry.

Results: In a previous study we compared PUR/CM and PUR/bioactive glass (BG) composites with a low (100 µg/mL) or high (400 µg/mL) dose of rhBMP-2 in a canine saddle defect model. For both PUR/CM and PUR/BG groups, a high dose of rhBMP-2 led to better preservation of the host ridge width as measured by µCT. PUR/CM composites (a slow-resorbing ceramic) led to improved space maintenance and more new bone than PUR/BG composites (a fast-resorbing ceramic). In the canine lateral ridge augmentation study, the compression-resistant PUR/CM composites are compared to an ACS (clinical control), which requires titanium mesh for space maintenance. To investigate dose dependence on new bone formation, the PUR/CM composite was augmented with 0, 200, or 400 μg/ml rhBMP-2. The canine lateral ridge augmentation study is designed to answer the following questions: (1) Will the biocomposite bone grafts maintain space and prevent prolapse in lateral ridge defects without protective membranes? (2) What is the optimal dose of rhBMP-2 from the PUR/CM composites? (3) How does defect healing compare between PUR/CM composites and the ACS control? In initial surgeries, clinical placement of the PUR/CM composites revealed the ease of conforming to the osseous defects. Once set, the composites maintained their shape during suturing and all sites healed satisfactorily. Preliminary µCT results at 16 weeks showed more new bone formation in high dose PUR/CM composites when compared to composites without rhBMP-2. Work is ongoing to test how the PUR/CM high dose composites compare to the ACS control.

Conclusions: PUR/CM composites with a high dose of rhBMP-2 support new bone formation and remodeling in a canine saddle defect model. We have applied this biocomposite to a canine lateral ridge augmentation model to test the hypothesis that the compression-resistant PUR/CM composite without protective membranes is an effective alternative for rhBMP-2 delivery compared to an ACS control.

Acknowledgements: This work was supported by the Armed Forces Institute of Regenerative Medicine (W81XWH-08-2-0034) and Medtronic, Inc.

References: 

1. von Arx T. Int. J. Oral Maxillofac. Surg 2002;31:190-199.

2. Li B. Biomaterials 2009;30:6768-6779.